The Promise of Long-Acting Injectable Antiretroviral Therapies

The Promise of Long-Acting Injectable Antiretroviral Therapies

In this HIV cases series, we highlight common patient case scenarios and the critical decision making that goes into selecting optimal patient management strategies. This case features an HIV-infected patient who is virologically suppressed on his current daily oral ART regimen but may be a candidate for future long-acting injectable therapy.

Case Details
A 45-year-old man is seen in follow-up for HIV infection. He has been stably suppressed for several years on various single pill treatments and currently is receiving rilpivirine (RPV)/emtricitabine/tenofovir alafenamide. He has normal renal and liver function tests. Although he has experienced no adverse events with his current ART regimen, each time he takes his medication, the process reminds him that he has a chronic, incurable, and stigmatized condition (HIV). He also finds taking the medication with food each day difficult, as sometimes he is dining with friends or colleagues who do not know he is HIV positive. He asks about alternative treatments that might one day be available that would free him from these difficult situations.

HIV-infected patients have expressed interest in therapies that can be taken less frequently than daily. This could mean long-acting injectables, implants, or even pills. Such interest stems, in part, from the desire for convenience, but also because fewer instances of medication mean fewer reminders of an HIV diagnosis. Given the interest, the many avenues currently exploring long-acting options are gratifying. The option furthest in clinical development is the long-acting cabotegravir plus RPV regimen, which is the focus of this commentary.

LATTE-2: Long-Acting Cabotegravir Plus Rilpivirine
This regimen was assessed in LATTE-2, a multicenter, open-label, randomized phase IIb study (N = 309). In this study, treatment-naive patients received oral cabotegravir plus abacavir (ABC)/lamivudine (3TC) in a 20-week induction phase (plus oral RPV from Weeks 16-20). Patients achieving virologic suppression during the induction phase were moved into the maintenance phase, where they were randomized to 4-week or 8-week intramuscular (IM) injections of cabotegravir plus RPV or continued oral administration of cabotegravir plus ABC/3TC. From a virologic standpoint, the study showed that patients who were virologically suppressed could be maintained on a cabotegravir plus RPV injectable and have virologic success similar to patients receiving oral therapy (Week 48 HIV-1 RNA < 50 copies/mL: 4-week IM cabotegravir plus RPV, 91%; 8-week IM cabotegravir plus RPV, 92%; oral cabotegravir plus ABC/3TC, 89%).

At Week 48, 8 patients (7%) receiving IM cabotegravir plus RPV every 8 weeks had protocol-defined virologic nonresponse, including a participant who rebounded with resistance to both cabotegravir and RPV, and only 1 patient receiving 4-week injections demonstrated virologic nonresponse. Because of this, the ongoing phase III ATLAS and FLAIR maintenance studies are using an injection frequency of every 4 weeks.

Aside from this increased injection frequency, what makes long-acting cabotegravir plus RPV potentially less appealing to our patients is that the 2 injections must be delivered in the gluteal region by a healthcare provider. Unlike a subcutaneous insulin shot, these agents are not self-administered. Of note, 99% of injection-site reactions in LATTE-2 were of grade 1/2 severity, and tolerability of IM cabotegravir plus RPV was good, with only 4% of patients discontinuing for adverse events (vs 2% in the oral arm). In terms of patient satisfaction, ≥ 85% of patients receiving IM cabotegravir plus RPV said they would be very satisfied to continue with their present form of treatment vs 55% in the oral treatment group.

To summarize the LATTE-2 findings:

• Similar virologic suppression was observed at maintenance Week 48 for 4-week and 8-week IM cabotegravir plus RPV and oral cabotegravir plus ABC/3TC
• The number of virologic nonresponders was greater with 8-week IM dosing vs 4-week IM dosing at maintenance Week 48, and thus, the 4-week schedule will be studied going forward
• 4% of patients discontinued for adverse events in the injectable therapy arms vs 2% in the oral arm
• ≥ 85% of patients receiving injectable treatment said they would be very satisfied to continue with their present form of treatment vs 55% receiving oral treatment

Moving Forward
If phase III study results mirror those observed in the phase II study, this regimen will be approved, and I am very glad to see the program moving forward. Although I am somewhat unsure about whether a 4-week, 2-injection strategy will be widely adopted for treating HIV-infected patients, there are certainly some patients for whom this strategy might be appropriate. Based on modeling, 8-week administration of single-agent cabotegravir is being explored in phase II/III trials for pre-exposure prophylaxis (PrEP). Because it is so adherence dependent, PrEP may be an excellent place for long-acting injectable therapy.

Additional Longer-Acting Agents
Additional agents with longer-acting potential that are in advanced clinical studies include anti-CD4 receptor antibodies such as VRC01, 3BNC117, and UB-421, and the novel NNRTI elsulfavirine.

Your Thoughts
Would you consider long-acting ART for your patients? What role do you think long-acting agents will play in the HIV treatment and prevention landscape? I encourage you to post your thoughts in the comments section below.